PARKIN modifies peripheral immune response and increases neuroinflammation in active experimental autoimmune encephalomyelitis (EAE)
PARKIN modifies peripheral immune response and increases neuroinflammation in active experimental autoimmune encephalomyelitis (EAE)
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DOI：
10.1016/j.jneuroim.2021.577694
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发表时间：
2021-08-24
影响因子：
3.3
通讯作者：
Hattori, Nobutaka
中科院分区：
文献类型：
--
作者：
Cossu, Davide;Yokoyama, Kazumasa;Hattori, Nobutaka
神经炎症在几种神经退行性疾病的发病机制中起重要作用。为了阐明线粒体自噬相关基因Parkin对神经炎症的影响，我们使用了实验性自身免疫性脑脊髓炎（EAE）的小鼠模型。用髓鞘少突胶质细胞糖蛋白免疫雌性Parkin- /-和雌性野生型对照小鼠以产生活性EAE。与野生型对照相比，Parkin-/-小鼠表现出更早的EAE发作和更严重的EAE，脾和脑中CD 8 α β +TCR α β + T细胞的数量大大增加，以及脾细胞中更强的T细胞增殖应答和改变的细胞因子分泌。此外，Parkin- /-小鼠在疾病的急性期显示出单核细胞/巨噬细胞和脊髓中活化的小胶质细胞的大量募集。他们还显示了在大脑中共表达M1和M2标记物的小胶质细胞的积累以及脊髓中A1反应性星形胶质细胞的强烈过度表达。此外，发生持续性疾病的Parkin-/-小鼠表现出神经胶质细胞数量减少和线粒体形态异常。我们的研究揭示了PARKIN蛋白在EAE期间调节外周免疫细胞介导的免疫中的作用，强调了其在神经炎症中的重要性，从而阐明了其在开发新型神经保护疗法中的潜力。
Neuroinflammation plays an important role in the pathogenesis of several neurodegenerative disorders. To elucidate the effects of the mitophagy-related gene Parkin on neuroinflammation, we used a mouse model of experimental autoimmune encephalomyelitis (EAE). Female Parkin- /- and female wild type control mice were immunized with myelin oligodendrocyte glycoprotein to develop active EAE. Compared to the wild type controls, the Parkin-/- mice showed an earlier onset and greater severity of EAE with a greatly increased number of CD8 alpha beta+TCR alpha beta+ T cells in the spleen and brain as well as a stronger T-cell proliferative response and an altered cytokine secretion in splenocytes. Furthermore, the Parkin- /- mice showed massive recruitment of monocytes/ macrophages and activated microglia in the spinal cord during the acute phase of the disease. They also showed accumulation of microglia co-expressing M1 and M2 markers in the brain and a strong over-expression of A1 reactive astrocytes in the spinal cord. Furthermore, the Parkin-/- mice that developed persistent disease exhibited reduced glial cell numbers and abnormalities in mitochondrial morphology. Our study sheds light on the role of PARKIN protein in modulating peripheral immune cells-mediated immunity during EAE, highlighting its importance in neuroinflammation, and thus elucidating its potential in the development of novel neuroprotective therapies.